Project Summary Alcohol use disorder is a chronic relapsing disorder that is a significant burden to afflicted individuals and society as a whole. Many adult alcoholics began to drink excessively during adolescence, and this early exposure may result in increased vulnerability to developing a lifelong addiction. The brain continues to mature throughout adolescence, and exposure to alcohol during this critical period may disrupt brain development, thereby predisposing the development of alcohol use disorder. For example, it has been suggested that the development of the medial prefrontal cortex (mPFC), a region critical to the regulation of motivated behaviors, can be adversely affected by cycles of alcohol intoxication and withdrawal during adolescence, and disrupted mPFC output is thought to contribute to the behavioral sequelae characteristic of alcohol use disorder. An understanding of how alcohol disrupts the maturation of the mPFC may therefore prove useful in preventing the transition to alcohol dependence. Toward this goal, the studies proposed in this application will make use of a mouse model of binge-like adolescent ethanol self-administration to identify the time course and behavioral consequences of chronic ethanol intake during this critical developmental period. Our lab has previously shown that adolescent binge-like alcohol intake disrupts the excitability of pyramidal neurons in the prelimbic area that form projections from the mPFC, and that perturbation of currents through hyperpolarization-activated cation channels (HCN channels) may underlie altered mPFC afferent output. Specific Aim 1 will use electrophysiological and immunohistochemical methods to determine the time course of ethanol-related disruption of mPFC HCN channels. Specific Aim 2 will determine whether the hyperpolarization of mPFC projections that arises from this ethanol-related disruption of HCN channels is responsible for the increased ethanol self-administration seen in adult animals with a history of binge-like adolescent intake. The results of these experiments could assist in the identification of novel therapeutic targets for alcohol addiction.